Laminitis is an extremely painful condition of the foot in horses. Its pathophysiology remains poorly understood, but involves both vascular and inflammatory events within the hoof leading to disruption of the lamellar dermo-epidermal junction, impaired biomechanical function, pain and substantial suffering (Hood et al. 1993; Hood 1999; Sumano Lopez et al. 1999; Parks & O'Grady 2003; Driessen et al. 2010). Ischemia and inflammation in the early stages of laminitis likely cause neuronal injury that eventually shifts the acute inflammatory pain into a chronic syndrome with a prominent neuropathic component (Moalem & Tracey 2006; Peroni et al. 2006; Belknap et al. 2007; Jones et al. 2007). The precise timing and nature of these events remain elusive. The response to treatment can be quite unpredictable. Such complexity makes pain management in horses with laminitis one of the biggest challenges in equine practice. Non-steroidal anti-inflammatory drugs (NSAID) are the mainstay analgesics for this condition. However, abridged efficacy against neuropathic pain and risks of dose-dependent gastrointestinal and renal adverse effects are significant limitations of these compounds (Sumano Lopez et al. 1999; Taylor et al. 2002; Driessen et al. 2010). These constraints often leave euthanasia as the only humane alternative to alleviate pain and suffering in affected horses (Driessen et al. 2010). This clearly underscores the need for the development of more efficacious and safer analgesics.
The oxidative metabolism of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (ARA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and linoleic acid (LNA) produces potent inflammatory mediators. Most of the analgesic research and drug development has focused on inhibiting ARA derivatives formed by cyclooxygenases (COX) (Tokuyama & Nakamoto 2011). Cytochrome P450 enzymes mediate another critical yet relatively unexplored pathway of PUFAs metabolism. This pathway transforms PUFAs into various biologically active compounds, including epoxy-fatty acids (EFAs or epoxides), such as epoxy-eicosatrienoic acids (EETs), or hydroxyl derivatives, such as hydroxy-eicosatetraenoic acids (HETEs) (Wagner et al. 2011b). These EFAs have multiple biological activities including the modulation of inflammation and nociceptive signaling (Murakami 2011). The biological activity of these epoxides is restricted as they are metabolized to the corresponding diols by the soluble epoxide hydrolases (sEH) (Wagner et al. 2011a). This has been confirmed with the development and use of sEH inhibitors (sEHis) (Morisseau & Hammock 2005; Hwang et al. 2007) in conditions involving several body systems and functions (Revermann 2010). The microsomal (mEH) and soluble (sEH) epoxide hydrolases were first thought to play a role in xenobiotic metabolism in mammalian tissues. Even though this is largely true for mEH, sEH has a minor role in xenobiotic metabolism. The major function of sEH is the degradation of endogenous lipid metabolites (Morisseau & Hammock 2008; Decker et al. 2009).